Notch Mediated Intercellular Communication and Cell Cycle Regulation

项目总结 通过信号通路对细胞增殖和分化的协调调节是 多细胞生物体的发展。此类法规的失败经常会导致 发育过程中的肿瘤形成或生长缺陷。Notch信号通路介导的信号转导 在正常情况下，细胞间的通讯对于广泛的生物过程是至关重要的 许多人类疾病的发展和发病机制，包括多种类型的癌症。 然而，它与细胞周期调控和生长控制的关系是复杂的，因为Notch可以发挥 要么是肿瘤抑制因子，要么是致癌作用。此外，关于是否以及如何 细胞周期机制反馈影响Notch信号转导。拟议的研究基于两项 在果蝇卵子发生模型系统中关于Notch调控的令人惊讶的初步发现，其中 Notch在细胞周期程序从有丝分裂到有丝分裂的切换中起着核心作用 上皮性毛囊细胞的内复制周期。我们发现染色质组装因子1(CAF-1) 同时作为抑制物和激活剂来调节毛囊细胞中Notch靶基因的表达。我们 还发现，细胞周期机制调节着Notch活性形式的稳定性，细胞质 域NICD。在这些新发现的基础上，提出了两个具体的目标来确定(1) Caf-1调控Notch信号的分子机制及(2)电位反馈 细胞周期机制对Notch稳定性和活性的影响。这两个目标都解决了重要的 Notch调控与细胞增殖控制有关的方面，但可以单独执行。这个 拟议项目的成果将有助于更好地理解Notch信号和细胞如何 循环机械在动物发育和组织动态平衡过程中相互作用。对这一问题的新见解 果蝇模型系统中Notch信号的调节将对生物医学产生积极影响 Notch通路与肿瘤发生和癌症密切相关的研究 发展。这些研究的发现将提供新的概念性理解 信号通路发挥其作用，以确保细胞和组织生长的正确决定， 对异常切迹相关疾病设计新疗法的几点认识 发信号。

PROJECT SUMMARY Coordinated regulation of cell proliferation and differentiation by signaling pathways is fundamental to the development of multicellular organisms. Failure in such regulations frequently lead to tumorigenesis or growth defects during development. The Notch signaling pathway mediated intercellular communication is critical for a wide range of biological processes during normal development and pathogenesis of numerous human diseases, including multiple types of cancer. However, its relationship with cell cycle regulation and growth control is complex since Notch can play either a tumor suppressor or an oncogenic role. Furthermore, little is known on whether and how the cell cycle machinery feeds back to influence Notch signaling. The proposed studies are based on two surprising preliminary findings on Notch regulation in the Drosophila oogenesis model system, where Notch plays a central role in controlling the switch of the cell cycle programs from mitosis to endoreplication cycles in epithelial follicle cells. We find that the Chromatin Assembly Factor 1 (CAF-1) acts as both a repressor and an activator to regulate Notch target gene expression in follicle cells. We also find that the cell cycle machinery regulates the stability of the active form of Notch, the cytoplasmic domain NICD. On the basis of these new findings, two specific aims are proposed to determine (1) the molecular mechanisms underlying CAF-1 regulation of Notch signaling and (2) the potential feedback mechanisms of the cell cycle machinery on Notch stability and activity. Both aims address important aspects of Notch regulation in relation to cell proliferation control, but can be executed separately. The outcomes of the proposed project will lead to improved understanding of how Notch signaling and cell cycle machinery interact during animal development and tissue homeostasis. The new insights into the regulation of Notch signaling in the Drosophila model system will have a positive impact on biomedical research due to the strong correlation of the Notch pathway with tumorigenesis and cancer development. The findings from these studies will provide new conceptual understandings of how signaling pathways exert their roles to ensure correct decisions in cellular and tissue growth, understandings which can be used to design novel therapies for diseases related to aberrant Notch signaling.